Living organisms from cyanobacteria to mammals display circadian rhythms (i.e., oscillations with 24-h periodicities) in multiple physiological and behavioral processes. These rhythms are found in nearly all living organisms. Circadian rhythms are generated endogenously and function under tightly regulated genetic control.
Circadian rhythms control a variety of biological processes, including sleep/wake cycles, body temperature, hormone secretion, gastrointestinal function, metabolic glucose homeostasis, and immunological functions. Biological clocks exhibiting circadian rhythms exist in virtually all tissues, with a series of clock genes generating the rhythm through protein feedback effects on their own synthesis.
These multiple endogenous clocks are distributed in every cell of the organism, which may result in each organ having its own timed circadian rhythm. A complex mechanism of activation and feedback regulate the expression, post-translational modification, translocation, and degradation of circadian proteins. The transcription factor CLOCK-BMAL1 is a core component of the molecular clock machinery that drives circadian gene expression and physiology in mammals. CLOCK and BMAL1 are each basic helix-loop-helix (bHLH) PAS-domain transcription factors that together form the positive elements of the central oscillatory loop. CLOCK and BMAL1 form a heterodimer that binds to E-box elements in the promoters of target genes. Some of the primary genes under transcriptional control by CLOCK:BMAL1 encode the three Period (mPer1, mPer2, and mPer3) proteins and two Cryptochromegenes (mCry1 and mCry2) proteins. Following translation of the Per and Cry proteins, they translocate to the nucleus where they act as potent inhibitors of CLOCK:BMAL1-induced gene transcription forming a negative feedback loop and regulating the rhythmic expression of many genes. The PERIOD protein mPER2, the gene of which is also under CLOCK:BMAL1 transcriptional control, functions as a stimulator of Bmal1 transcription, forming the positive feedback loop and enhancing CLOCK:BMAL1 activity. The regulation of these positive and negative feedback loops regulates the circadian rhythm within the cell.
SIRT1, a nicotinamide adenine dinucleotide-dependent sirtuin, has been shown to promote cell survival by inhibiting apoptosis or cellular senescence in mammalian cells. Recent studies have provided a link between the cellular metabolic function of SIRT1 and the circadian rhythm (controlled by the CLOCK:BMAL1 machinery) where it has been shown that SIRT1 controls circadian clock circuitry and promotes cell survival providing a connection with age-related neoplasms. Also, circadian function decays with aging in normal mice, and boosting their SIRT1 levels in the brain could prevent this decay. Conversely, loss of SIRT1 function impairs circadian control in young mice, mimicking what happens in normal aging. Moreover, SIRT1 has been shown to exert this control by regulating the genes BMAL1 and CLOCK, the two major keepers of the central circadian clock.
Oxygen and circadian rhythmicity are essential in a myriad of physiological processes to maintain homeostasis, from blood pressure and sleep/wake cycles, as well as in cellular signaling pathways that play critical roles in health and disease. Oxidative stress can induce the dysregulated circadian rhythms. Thus, there is a need for new compositions and methods for regulating proper protein expression and circadian rhythm.